HIV-1 infection of the central nervous system occurs in a majority of AIDS patients, and causes a variety of neurologic dysfunction and neuropathologies. Microglia/macrophages are the major target cells for I-IIV-I infection. It has generally been accepted that neurons that are mostly affected in the brain of HIV-positive individuals are rarely infected by HIV-1. Therefore, a number of indirect mechanisms have been proposed for AIDS-associated neuropathogenesis. Among these is the soluble viral protein Tat. We have recently shown that HIV-1 Tat protein interacts with low-density protein receptor-related protein (LRP) and results in neuronal uptake of Tat protein. Moreover, Tat interaction with LRP leads to extracellular accumulation of LRP physiological but neurotoxic ligands, suggesting that AIDS-associated neuropathology and other neurodegenerative diseases such as Alzheimer's disease, may share a common pathway that eventually leads to dementia. Our preliminary studies demonstrated that Tat expression in the brain of doxycycline (Dox)-regulated, brain-targeted Tat transgenic mice results in neuropathologies, reminiscent of those noted in the brain of AIDS patients. The underlying hypothesis for this proposal is that Tat interaction with LRP contributes to AIDS-associated neuropathological disorders including dementia. We propose that HIV-1 Tat protein is a major neuropathogenic factor contributing to HIV-associated neuropathology. To test this hypothesis, we propose the following interrelated specific aims: 1) To determine gene expression by LRP-uptaken Tat; 2) To determine LRP-mediated intracellular signaling elicited by Tat binding; and 3) To determine mechanisms of Tat-induced neuropathology. Experimental approaches include use of the primary mouse cortical neuron cultures, Tat-expressing stable cell lines, and the Dox-regulated, brain-targeted Tat transgenic mouse model. This combined molecular, cellular, biochemical, and genetic approach will provide a better and unique understanding of the highly important and pervasive HIV-1 Tat protein, and its role in HIV-l-induced neuronal injury and neurologic symptoms of AIDS patients. In addition, these studies will also yield new clues for developing anti-HIV therapeutic strategies for treating HIV-associated neurological disorders occurring in the majority of AIDS patients.